The preparation of [1,2,4]triazolo[1,5-a]pyrimidines catalyzed by Schiff base zinc(ii) complex supported on magnetite nanoparticles under mild conditions

Nano-[CuFe2O4@SiO2/propyl-1-(O-vanillinaldimine)][ZnCl2] was prepared by placing a Schiff base zinc(ii) complex on a magnetite core and fully characterized by various analyses such as FT-IR, FE-SEM, EDAX, SEM-coupled EDX, TGA, VSM and TEM. The complexes supported on silica-coated magnetite copper ferrite nanoparticles were used as a reusable catalyst for the synthesis of 5-methyl-N,7-diphenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a] pyrimidine-6-carboxamides resulting in 40% to 96% yield in the reactions of various aldehydes, acetoacetanilide, and 3-amino-1,2,4-triazole at 60 °C under solvent-free conditions. The zinc complex can change its structure from tetrahedral to square planar and catalyze the reaction. Some products containing the benzyloxy moiety are new and have been reported for the first time.


Introduction
Recently, the preparation and application of nano magnetic materials in various domains of sciences has attracted the attention of scientists.Nano magnetic materials have been used as effective catalysts to promote organic transformations.0][11][12] One of the categories of the catalysts with all these features is the magnetic catalyst, or catalyst supported on a magnetic surface.Such catalysts are also easily attracted by an external magnet from the reaction mixture owing to their magnetic properties. 6,7,13,14One of these catalysts that has the potential to be bonded to a magnetic surface is Schiff base complexes.One of the most important features of catalysts supported on magnetic surfaces is the ease of separation from the reaction mixture and potential for reuse in other reactions, which reduces material consumption and enhances atomic economy. 6,7Schiff base complexes comprise an organic part and a metal, whereby the organic part is a ligand, which is formed from the combination of a primary amine and a carbonyl compound.Some Schiff base ligands have medicinal properties such as antifungal, 15,16 antibacterial, 17 antiviral 18 and antioxidant properties. 18][20][21][22][23] Today, multi-component reactions are considered as an efficient method in organic synthesis and the production of biological compounds and essential drugs.This protocol has some important advantages such as reduction of energy and time consumption, high efficiency, easy purication of the products and reduction of waste material production without the production of side products.][26][27][28][29][30][31] Phenyl- [1,2,4]triazolo [1,5-a]pyrimidine-6-carboxamide compounds have some signicant activities and are widely used in medicinal chemistry. 32Triazolopyrimidine derivatives are known to be blood pressure regulators, 33 antibacterial agents, 34 anticancer agents, [35][36][37] antidiabetics agents, 38 antiproliferative agents, 39 have anti-tumor activity, 40 protein kinase inhibitors, 41 antifungal agents, 42 and macrophage activators. 43,44Phenyl- [1,2,4]triazolo [1,5-a]pyrimidine-6-carboxamide has been previously produced through the multi-component synthesis of acetoacetanylide, 3-amino [1,2,4]triazole and aldehydes using various catalysts such as p-toluenesulfonic acid, 45 HCl, 46 maltose, 47 and triethylaminium-N-sulfonic acid tetrachloroaluminate. 48 Considering the importance of this category of triazolopyrimidine compounds in medicinal chemistry, new preparation methods are required for them.
Keeping this need in mind, we prepared a new Schiff base zinc(II) complex supported on magnetite nanoparticles and successfully used it as a heterogeneous catalyst for the preparation of phenyl- [1,2,4]triazolo [1,5-a]pyrimidine-6-carboxamide at 60 °C under solvent-free conditions (Scheme 1).

Materials
All materials were purchased from Merck and used without further purication; their purity was, however, checked by thinlayer chromatography (TLC).

Instrumental
The melting point of products were measured by electrothermal IA 9100 device.The FT-IR spectra of compounds were recorded by a Thermo device (model Avatar) spectrometer. 1 H NMR and 13 C NMR spectra were recorded on Bruker DRX-250 Avance with DMSO as a solvent.

Catalyst synthesis
2.3.1 General method for the synthesis of CuFe 2 O 4 .To a mixture of FeCl 3 $6H 2 O (1.0 mmol) and CuCl 2 $2H 2 O (0.5 mmol), 5 ml of NaOH (0.2 M) and 9 ml of distilled water were added, and the reaction mixture was stirred under an atmosphere of nitrogen for 5 h at 90 °C.Aer this time, the prepared particles were ltered, dried, and calcinated in a thermal oven at a 700 °C for 5 h.
2.3.2General method for the synthesis of CuFe 2 O 4 @SiO 2 core-shell.CuFe 2 O 4 nanoparticles (2 g) were dispersed in a mixture of ethanol and water (200 : 10 v/v) using an ultrasonic bath for 10 minutes.Then, 6.64 ml of ammonia solution (25%) and tetramethyl orthosilicate (2 ml) were added dropwise to the mixture and stirred for 24 hours at room temperature.Finally, the obtained CuFe 2 O 4 @SiO 2 nanoparticles were heated at 60 °C in vacuum oven for 3 hours to remove the solvent.

Synthesis of (OEt) 3 Si/propyl-1-(O-vanillinaldimine).
(3-Aminopropyl)triethoxysilane (1.0 mmol) and ortho-vanillin (1.0 mmol) were added into a round-bottomed ask connected to a reux condenser and stirred at room temperature for 24 hours, under solvent-free conditions.Finally, the obtained product was dried at room temperature as a Schiff base ligand.The structure of the Schiff base ligand was conrmed by FT-IR and 1 H NMR.
2.3.4The metallization of (OEt) 3 Si/propyl-1-(O-vanillinaldimine).To a round-bottomed ask containing the prepared ligand (2.0 mmol) and zinc chloride (1.0 mmol), a few drops of ethanol as a solvent were added and stirred at 70 °C for 24 hours to yield the Schiff base complex.

Synthesis of nano [CuFe
SiO 2 nanoparticles (2 g) were dispersed in toluene (15 ml) for 20 minutes.Then, the prepared Schiff base complex (1.0 mmol) was added to the mixture and stirred for 24 hours under reux conditions at 110 °C.Finally, the obtained nanomagnetic Schiff base complex was collected by an external magnet and washed with ethanol (15 ml) (three times) and dried at 60 °C. 3 Results and discussion

Synthesis and characterization of catalyst
In this research, a Schiff base complex of zinc(II) was synthesized and supported on magnetite nanoparticles for use as a reusable catalyst in organic reactions.To create the catalyst, a Schiff base ligand was rst synthesized by the reaction of 3aminopropyl triethoxysilane with ortho-vanillin.Metalation of the presented ligand was then performed by adding ZnCl To show the specic bonds in the structure of the supported catalyst, the FT-IR spectrum of [CuFe 2 O 4 @SiO 2 /propyl-1-(Ovanillinaldimine)][ZnCl 2 ] was recorded and the important peaks were studied (Fig. 1).As shown in Fig. 1, the peaks at about 591 and 1099 cm −1 are related to Fe-O and Si-O bond vibrations, respectively.The peak at about 2929 cm −1 corresponds to the C-H bond vibration.Moreover, the peak at about , which is coordinated with zinc chloride (Fig. 1).In Fig. 1, the FT-IR spectrum of the catalyst was compared with other species in the structure of the catalyst to show the changes that had occurred in its structure.
Energy-dispersive X-ray spectroscopy (EDX) analysis was used to determine the elements present in the structure of From the results of this analysis, it was determined that the structure contains various elements, including copper, iron, oxygen, nitrogen, carbon, silicon, zinc and chlorine (Fig. 2).
SEM-coupled EDX (SEM mapping) was among other analyses conducted to determine the elements present and how they are distributed in the structure of the catalyst.The relevant images are shown in Fig. 3.
Field-emission scanning electron microscopy (FE-SEM) analysis was used to check the morphology and size of the particles on the surface of the catalyst.From this investigation, it was found that the particles were formed in sizes <100 nm (Fig. 4).
To determine the thermal stability of the catalyst and its usability in various reactions, thermal gravimetric analysis (TGA) was performed on the catalyst.From the results obtained from this analysis, the designed catalyst can be used in temperatures of up to 300 °C (Fig. 6).Based on the results obtained from the TGA analysis, this catalyst shows acceptable thermal stability in chemical reactions.
The magnetic behavior of the nano magnetite catalyst was measured using a vibrating sample magnetometer (VSM) at room temperature.The saturation magnetization for [CuFe 2 -O 4 @SiO 2 /propyl-1-(O-vanillinaldimine)][ZnCl 2 ] was found to be Fig. 1 The FT-IR spectrum of nano magnetic catalyst in comparison with other species in the catalytic structure.
Fig. 2 The EDX analysis of nano magnetite Schiff base complex.] in chemical reactions, this catalyst was used in the synthesis of [1,2,4]triazolo [1,5-a]pyrimidines.At rst, to nd the best reaction conditions, the reaction between 4-nitrobenzaldehyde with acetoacetanilide and 3-amino-1,2,4triazole was chosen as a model reaction and the effects of the amount of catalyst, solvent and temperature were studied in this reaction (Table 1).As indicated in Table 1, the best result was achieved in the presence of 0.003 g of the catalyst at 60 °C under solvent-free conditions.Various solvents such as CHCl 3 , ethanol, ethyl acetate, and n-hexane were used in this reaction in comparison with the solvent-free condition, all of which did not have acceptable results.

Synthesis of [1,2,4]triazolo[1,5-a]pyrimidines
Aer the optimization of the reaction conditions, various aryl aldehydes containing electron-withdrawing groups, electrondonating groups, and halogens were used in the reaction with acetoacetanilide and 3-amino-1,2,4-triazole under the optimized reaction conditions for the preparation of [1,2,4]triazolo [1,5-a]pyrimidines (Table 2).As shown in Table 2, some aryl aldehydes containing various benzyloxy substitutions on their rings were successfully used in this reaction for the preparation of some new [1,2,4]triazolo[1,5-a]pyrimidines, which were not reported at all.As depicted from the results in Scheme 3, was successfully used in the reaction to give the products in high yields and short reaction times.
Regarding the proposed mechanism of this reaction, it should be mentioned that due to the presence of bulky groups on nitrogen atoms in the structure of the catalyst, the zinc complex can change from a tetrahedral structure to a square planar structure to reduce repulsion (Scheme 3).Then, the zinc metal accepts acetoacetanilide and aldehyde compounds as ligands in the cis position relative to each other.In the next     Then, with the intramolecular nucleophilic attack in this intermediate, the desired product is formed and separated from the zinc complex.Finally, the chloride anions in the reaction media return to the complex structure (Scheme 4).

Efficiency of catalyst
One of the important advantages of magnetic catalysts is their reusability in chemical reactions.For this purpose, the recovery of the catalyst in the model reaction was studied.In this study, aer the completion of the reaction, the reaction mixture was extracted using hot ethanol and separated from the catalyst.The isolated catalyst was reused in another reaction aer washing with acetone.This catalyst was reused three times without a signicant decrease in reaction efficiency (Fig. 8).
To nd the reason for the decrease in the product yield aer the reuse of catalyst, the leaching of zinc on the catalyst surface was studied by atomic absorption spectroscopy.According to this study, zinc constituted 1.38% of the fresh catalyst and there was a 0.64% gain in the amount of zinc on the reused catalyst aer four runs.Therefore, one of the reasons for the decrease of yield of product can be attributed to leaching of zinc onto the catalyst surface.
To show the superiority of the new method over the previous methods, the results obtained with the nano magnetite Schiff base complex as a catalyst were compared with some catalysts used in the reaction of 4-nitrobenzaldehyde with acetoacetanilide and 3-amino-1,2,4-triazole.In the third method, acetoacetanilide was in situ prepared in the reaction.As can be summarized from Table 3, the presented method is superior to the other catalysts in terms of the isolated yield of the related product and reusability of the catalyst.

Fig
Fig. SEM-coupled EDX (SEM mapping) of the nano magnetite Schiff base complex.

Fig. 5
Fig. 5 TEM image of nano magnetite Schiff base complex.

Scheme 4 Fig. 8
Scheme 3The transformation from a tetrahedral to a square planar for zinc complex.

Table 1
The effect of temperatures, solvents and various amount of catalyst on the reaction of 4-nitrobenzaldehyde with acetoacetanilide and 3-amino-1,2,4-triazole a Isolated yield.

Table 3
The comparison of the presented catalyst to some other catalysts on the reaction of 4-nitrobenzaldehyde with acetoacetanilide and 3amino-1,2,4-triazole